Effects of essential aminoacid (EAA) restriction on cognitive function, ageing and neurodegeneration.

The developed world is currently facing a significant increase in average lifespan, with the implication of increased age-related diseases including various cancers, dementia, and type 2 diabetes in our aged population. Thus, understanding the mechanisms and pathways underlying lifespan regulation is crucial for improving health over this extended life.
Aging is characterized by increased oxidative stress and brain inflammation alongside adiposity and insulin resistance which may play a role in regulating lifespan and resilience. Importantly, ageing is the principle risk factor for many disease including dementia, yet, the role of dietary factors and homeostatic control is not well understood.
Dietary methionine restriction (MR) (from 0.86% to 0.172% of total diet) has been reported to decrease body weight and adiposity, and improve glucose tolerance in rodents. We recently demonstrated that MR feeding in aged rodents (>12 months old) can completely reverse age-induced increase in adiposity and metabolic dysfunction (Lees et al, 2014). Similarly to caloric restriction, MR extends lifespan but is accompanied by increased food intake and energy expenditure. However, whether these effects occur with the restriction of any essential amino acid (EAA) or are specific to methionine remains unknown. Equally, it is unclear whether this would lead to improved resilience against brain pathologies as seen in Alzheimer’s disease.
The aim of this project is therefore to investigate the effects of EAA restriction on cognitive and motor impairments due to ageing and dementia-relevant phenotypes. We will assess whether deficits can be prevented or reversed in aged mice or transgenic models of AD (knock-in and over-expression lines for tau, beta-amyloid and BACE1, e.g. Plucinska et al., 2016) with dietary interventions such as MR. We will examine the effects of EAA restriction in old, middle-aged and young wild-type and transgenic mice, with specific emphasis on hippocampal function, neuro-inflammation and ER stress pathways. In addition to in vivo physiological endpoints we seek to perform tissue- and brain-region specific analysis using a range of molecular techniques. Overall, we aim to build a systems understanding of dietary impact on ageing and degenerative pathologies that is informative for human health.
The successful candidate would obtain excellent training in behavioural and physiological in vivo assessments (activity, cognitive and motor phenotyping, glucose and lipid metabolism assessments), microscopy (imaging, microscopy & histology), biochemical and molecular assays (Western blotting, ELISA, protein arrays), and molecular biology techniques (microarrays, qPCR, RNAseq).

APPLICATION PROCEDURE:
This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: https://www.abdn.ac.uk/pgap/login.php. You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM.

Candidates should contact the lead supervisor to discuss the project in advance of submitting an application, as supervisors will be expected to provide a letter of support for suitable applicants. Candidates will be informed after the application deadline if they have been shortlisted for interview. Interviews are expected to take place on 23rd or 24th July 2019.